ASUNTOS REGULATORIOS PRODUCTOS. Docente a cargo: Mario Malaspina

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1 CARRERA DE ESPECIALIZACION EN BIOTECNOLOGIA INDUSTRIAL FCEyN-INTI Materia de Articulación CEBI_E6E6 ASUNTOS REGULATORIOS PRODUCTOS BIOTECNOLOGICOS Docente a cargo: Mario Malaspina CEBI_E6_2 : Registro de Medicamentos de Origen Biotecnológico. Regulatoria en Nuestro País. Parte lii: Marco Internacional

2 CUAL ES EL CONFLICTO EN ESTE MOMENTO? Aparición del borrador de la guía: EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, 19 to 23 October 2009 Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs) This document has been prepared for the purpose of inviting comments and suggestions on the proposals contained therein, which will then be considered by the Expert Committee on Biological Standardization (ECBS). The text in its present tform does not necessarily represent an agreed dformulation of fthe Expert Committee. Comments proposing modifications to this text MUST be received by 9 October 2009 and should be addressed to the World Health Organization, Y PORQUE ES EL CONFLICTO?? LA PROXIMA.CLASE. Parte III MARCO INTERNACIONAL

3 EEUU: FOOD AND DRUG ADMINISTRATION

4 FDA: UN POCO DE HISTORIA O EN TODAS PARTES SE CUECEN HABAS I 1927 La "Oficina de Química" es reorganizada en dos entidades. Las funciones regulatorias se en la "Food, Drug and Insecticide Administration" (Administración de Alimentos, Drogas e Insecticidas) y las no regulatorias en la "Bureau of Chemistry and Soils" (Oficina de Química y Desechos) El nombre "Food, Drug and Insecticide Administration" es recortado a "Food and Drug Administration" (FDA) 1938 Más de 100 personas mueren después de haber consumido un sulfa-elixir con sabor a frambuesa, el cual había sido introducido al mercado por la S.E. Massengill Company sin las pruebas correspondientes. Alrededor del 70% del elixir era dietilenglicol, producto altamente tóxico. Como consecuencia del escándalo y protesta públicos se promulgó el "Acta Federal de Alimentos, Drogas y Cosméticos" (Federal Food, Drug, and Cosmetic Act) de 1938, la cual daba poder a la FDA de pre-aprobar todas los nuevos medicamentos introducidos en el mercado interestatal.

5 CBER: Vacunas, Hemoderivados y Biológicos

6 Aspectos Regulatorios En USA, las proteínas y los péptidos son aprobados por la FDA como NDA ( New Drug Application, section 505) o como BLA (Biological Licence Application, section 351 PHA Public Health Service Act). Sin embargo, se les escaparon un para como ANDA Abreviated New Drug Application antes de que se generara la gran discusión.

7 Comparability The current FDA use of the term comparability generally refers to the comparison of a biological product before and after a manufacturing change by the manufacturer. A sponsor may be able to demonstrate that a product made after a manufacturing change is comparable to a product made before implementation of the change. This may be demonstrated t d through h different types of analytical and functional testing and might not require additional clinical studies. The Agency may determine that the two products are comparable if the results of the comparability testing demonstrate that the manufacturing change does not affect safety, identity, purity, or potency. (It is important to note, however, that this has generally been applied in cases where the manufacturer and Agency have full access to the manufacturer s data something that may not be the case for follow-on products.) See April 1996 FDA Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products.

8 However, a number of important issues related to development of such follow-on products also have been identified. First, there is general recognition that the idea of sameness, as the term is used in the generic drug approval process under the Federal Food, Drug, and Cosmetic (FDC) Act and applied to small molecules, will not usually be appropriate for more structurally complex molecules of the type generally licensed as biological products under the Public Health Service (PHS) Act Traditionally, some natural source proteins have been regulated as drugs under the FDC Act, including insulin, hyaluronidase, menotropins, and human growth hormones, while other natural source proteins, such as blood factors, are regulated as biological products under the PHS Act.

9 Proteínas recombinantes Fortical: (calcitonina i de salmón, spray nasal): la FDA consideró que en base a una completa caracterización fisicoquímica, estructura primaria, secundaria y terciaria, Fortical era indistinguible de Miacalcin c NS. Los estudios farmacocinéticos y farmacodinámicos y de inmunogenicidad en animales demostraron comparabilidad entre ambos productos

10 Proteínas recombinantes Omnitrope (somatropin): fue la primer hormona de crecimiento humana recombinante en ser aprobada como ANDA FDA 505(b)(2) ) tomando como producto de referencia o similar a Genotropin rh-gh, aprobado por FDA para la misma indicación.

11 Producto Droga Aprobación MW (Da) Proteínas no glicosiladas Forteo Teriparatide NDA Byetta Exenatide NDA Lantus Insulina Glargina NDA Betaseron Interferon ß -1b BLA Genotropin Somatotropin NDA Proteínas Glicosiladas il Rebif Interferon ß -1a BLA Epogen/Procrit Epoetin α BLA Enbrel Etanercept BLA Proteínas PEGiladas PegIntron PegInterferon α-2b BLA Neulasta Pegfilgrastim BLA Anticuerpos Monoclonales Rituxan Rituximab BLA Avastin Bevacisumab BLA Erbitux Cetuximab BLA

12 EMEA: COMUNIDAD ECONOMICA EUROPEA p

13 EUDRALEX: LEGISLACION DE EMEA eudralex/eudralex_en.htm d l

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17 Guidelines /humanguidelines/biologicals.htm

18 GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS For the Marketing Authorisation Applications (MAAs) based on the demonstration of the similar nature of the two biological medicinal products. Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the new similar biological medicinal product and the chosen reference medicinal product authorised in the Community.

19 GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS CONTAINING BIOTECHNOLOGY- DERIVED PROTEINS AS ACTIVE SUBSTANCE: NON-CLINICAL AND CLINICAL ISSUES Similar biological medicinal products are manufactured and controlled according to their own development. An appropriate comparability exercise `will be required to demonstrate that the similar biological and reference medicinal products have similar profiles in terms of quality, safety and efficacy. The quality issues relevant for demonstration of comparability for similar biological medicinal products containing recombinant DNA-derived proteins are addressed in the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: quality issues (EMEA/CHMP/49348/05). The Marketing Authorisation (MA) application dossier of a biological medicinal product claimed to be similar to a reference medicinal product already authorised shall provide a full quality dossier. Comparable clinical efficacy and safety has to be demonstrated. The principles for this exercise are laid down in this guideline. Product class specific annexes will supplement this guideline where a need has been or will be identified. d The same reference medicinal product should be used for all three parts of the dossier (i.e. quality. safety and efficacy aspects). In case the originally authorised medicinal product has more than one indication, the efficacy and safety of the medicinal product claimed to be similar has to be justified or, if necessary, demonstrated separately for each of the claimed indications.

20 EMEA Marco Regulatorio Cada producto biosimilar es analizado a través de Guías específicas para Biosimilares caso por caso Guidelines on Similar Biological Medicinal Products Guidelines on SBMP containing biotechnologicalderived proteins as Active Substance Quality issues Non-Clinical i l and Clinical i l issues Annex to guideline on SBMP Adopción de ICH-Q5E como Guía de Comparabilidad

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22 ICH: COMITÉ INTERNACIONAL DE ARMONIZACION

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24 S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Product Q5E: Comparability of Biotechnological/Biological Products subject to changes in their manufacturing Q5D: Quality of Biotechnological/Biological Prod.: Derivation and Characterisation of Cell Substrate Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products Q5B: Analysis of the Expression Construct in Cells Used for Production of r-dna (Biotechnological) Q5A(R1): Viral Safety Evaluation of Biotechnology Products

25 PIC/s: ESQUEMA COOPERATIVO DE INSPECCIÓN h /

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28 WHO: ORGANIZACIÓN MUNDIAL DE LA SALUD (OMS) html

29 OPS: ORGANIZACIÓN PANAMERICANA DE LA SALUD org/hq/index php?lang=es

30 ARGENTINA Y LA OMS PORQUE LA OMS NOS COMPROMETE? PETENECER A LA RED PANAMERICANA PARA LA ARMONIZACIÓN DE LA REGULACIÓN FARMACÉUTICA (RED PARF) 2002 Disposición Nº 2309/02 Aprueba el documento Buenas Prácticas de Fabricación y Control de Medicamentos OMS 92, (Resolución GMC Nº 61/00) BO.- 21/06/ Disposición N 1930/95 Cumplimiento de BPFyC, OMS

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35 PHARMACOPOEIAS: FARMACOPEAS 1.- BRITISH PHARMACOPOEIA: Capítulos particulares por activos 2.- UNITED STATES PHARMACOPOEIA: capítulo general de biológicos 3.- EUROPEAN PHARMACOPOEIAS: Capítulos particulares por activos. 4.- FARMACOPEA ARGENTINA VII: Capítulos generales. Ninguna codifica Productos terminados Hay que tener en cuenta los FORUM

36 MERCOSUR: MERCADO COMUN DEL SUR

37 XXIX REUNIÓN ORDINARIA DEL SGT Nº 11 SALUD / COMISIÓN DE PRODUCTOS PARA LA SALUD La Delegación de Brasil, en consonancia con lo acordado en la XXVIII Reunión Ordinaria, recordó que la información a remitir por los países incluye: la comparación entre las recomendaciones de OPS y lo efectivamente aplicado y no aplicado por cada Estado Parte expresadas en forma de cuadro a fin de facilitar su consolidación la visión global de cada país, desde el punto de vista estratégico, sobre sus fortalezas y debilidades d en el tema. El cuadro incluye iniciativas previstas por OMS e ICH y aspectos relacionados con la biotecnología, además de los previstos por la OPS. En el área de estudios clínicos y estabilidad, se siguen las recomendaciones de OMS e ICH.

38 ENTONCES: CUAL ES EL CONFLICTO EN ESTE MOMENTO? Aparición del borrador de la guía: EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, 19 to 23 October 2009 Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs) This document has been prepared for the purpose of inviting comments and suggestions on the proposals contained therein, which will then be considered by the Expert Committee on Biological Standardization (ECBS). The text in its present form does not necessarily represent an agreed formulation of the Expert Committee. Comments proposing modifications to this text MUST be received by 9 October 2009 and should be addressed to the World Health Organization,

39 COMENTARIOS AL DOCUMENTO DE OMS Recently, the expiration of patents and/or data protection for the first major group of originator s biotherapeutics has ushered in an era of products that are designed to be similar to a licensed originator product. El documento para fundamentar las acciones que habría que realizar para aprobar un biosimilar se centra exclusivamente en la experiencia de los países centrales y desconoce absolutamente lo sucedido con biosimilares en países como Argentina. Esto queda plasmado en forma prístina en el primer párrafo de la introducción, líneas 67 y 68 que dicen

40 COMENTARIOS AL DOCUMENTO DE OMS Considerations for choice of reference biotherapeutic product en donde dice The choice of RBP should not infringe on patents or intellectual property in the jurisdiction it is registered nor bypass those of the jurisdiction in which the SBP will be marketed y se vuelve a remarcar en el apartado Roles and responsibilities of NRAs donde dice: The licensing of SBPs should be consistent with the laws and regulations for patents, intellectual property, and data protection (where they exist) (líneas 1053 a 1055) 1.- Antepone intereses económicos a intereses de salud pública Desconoce las experiencias hechas en países como Argentina 3.- Coloca a las industrias locales y porque no también a las autoridades sanitarias nacionales en una situación de Compromiso.

41 COMENTARIOS AL DOCUMENTO DE OMS Based on current understanding and limited experience with SBPs, automatic ti substitution of an originator i product with a SBP at the pharmacy level is not recommended at this time. Decisions regarding automatic substitution of SBPs should be made by health authorities in each country taking into account the pharmacovigilance system in place, patient safety and other relevant factors. (Líneas 277 a 281) A que limitado conocimiento y experiencia se refiere el documento en este párrafo? En Argentina si tomamos como ejemplo la EPO deberíamos plantear lo opuesto ya que las unidades comercializadas de los biosimilares son mucho mayores que la de los originales

42 COMENTARIOS AL DOCUMENTO DE OMS However, even minor differences in the manufacturing process may affect the pharmacokinetics, pharmacodynamics, efficacy and/or safety of biotherapeutic products. As a result, it has been agreed that the normal method for licensing generic medicines through bioequivalence studies alone is not scientifically appropriate p for SBPs Esta afirmación es el caballito de batalla argumental de las empresas que desarrollaron los medicamentos biotecnológicos originales, que de tanto repetirla en diferentes ámbitos pareciera que pasó a ser una verdad

43 Y ENTONCES VOLVEMOS PORQUE ES EL CONFLICTO?? LA PROXIMA.CLASE. Parte IV ENSAYOS CLINICOS Y DOSSIER FORMATO CTD

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